Sertraline is a known compound having the following structure:

Sertraline has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine. Sertraline and its pharmaceutically acceptable acid addition salts, such as the hydrochloride salt, are disclosed in U.S. Pat. No. 4,536,518, which issued on 20 Aug. 1985, (hereafter referred to as the '518 patent), which is herein incorporated by reference in its entirety. Another pharmaceutically acceptable salt of sertraline is the mesylate salt.
The '518 patent states that sertraline and derivatives thereof are useful as antidepressant agents. U.S. Pat. No. 5,130,338, which issued on 14 Jul. 1992, refers to the use of sertraline to treat chemical dependencies, including dependencies on alcohol, tobacco and cocaine. U.S. Pat. No. 4,962,128, which issued on 9 Oct. 1990, refers to the use of sertraline to treat anxiety related disorders such as panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, phobias, post traumatic stress disorder and avoidant personality disorder. U.S. Pat. No. 4,940,731, which issued on 10 Jul. 1990, refers to the use of sertraline to treat premature ejaculation. Published PCT patent application, WO 96/22085, which was published on 25 Jul. 1996, refers to the use of sertraline to treat cancer patients. Published European patent application 0768083, which published on 16 Apr. 1997, refers to the use of sertraline to treat post myocardial infarction patients.
U.S. Pat. No. 5,597,826, which issued on 28 Jan. 1997, relates to novel compositions containing a serotonin selective reuptake inhibitor (SSRI), such as sertraline, and an agonist or antagonist of the serotonin 1 (5-HT1) receptor and to the use of such compositions for treating or preventing a condition selected from mood disorders, including depression, seasonal affective disorders and dysthmia, anxiety disorders, including generalized anxiety disorder and panic disorder; agoraphobia, avoidant personality disorder; social phobia; obsessive compulsive disorder; post-traumatic stress disorder; memory disorders including dementia, amnestic disorders and age-associated memory impairment; disorders of eating behavior, including anorexia nervosa and bulimia nervosa; obesity; cluster headache; migraine; pain; Alzheimer's disease; chronic paroxysmal hemicrania; headache associated with vascular disorders; Parkinson's disease, including dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; endocrine disorders such as hyperprolactinaemia; vasospasm (particularly in the cerebral vasculature); hypertension; disorders in the gastrointestinal tract where changes in motility and secretion are involved; sexual dysfunction, including premature ejaculation; and chemical dependencies. The foregoing published applications and U.S. patents are herein incorporated by reference in their entireties.
As noted above, sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration. (Physicians' Desk Reference (PDR), 52nd ed., Supplement A, pages A250–A255 (1998).) Its mechanism, pharmacokinetics, and metabolism confer safety, once-daily dosage and efficacy in the treatment of depression, obsessive compulsive disorder and panic disorder. It is approved for the treatment of one or more of these indications in over 60 countries worldwide. The daily doses for sertraline, expressed as the free base, range from 50–200 mg, increasing in 50 mg increments. A titration dose of 25 mg/day during the initial phase of therapy may be warranted in some indications.
Tablet and capsule formulations of sertraline hydrochloride are commercially available in different countries. Capsular-shaped, scored tablets are available in strengths of 50 and 100 mg and are sold under the brand name, ZOLOFT® Tablets, in the U.S. The capsules are available in some countries in strengths of 50 mg and 100 mg.
The '518 patent discloses that sertraline and related compounds can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. According to this patent, when aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening, or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
However, development of an oral liquid dosage form of sertraline has been complicated by the objectionable bitter taste and astringency sensation imparted by the drug in liquid form. Thus, direct (“ready-to-use”) oral liquid solutions or suspensions of sertraline, such as those described in the '518 patent above, have an objectionable taste, despite the inclusion of a variety of taste-masking or flavoring agents.
An oral liquid dosage form of sertraline with acceptable taste would be a valuable addition to the existing formulations, providing greater choice for both the prescriber and the patient. This is of importance with regard to the issue of non-compliance with treatment, which is believed to affect up to 50% of outpatients and appears to be a particular problem with elderly, pediatric and psychiatric patients (B. Blackwell, Drug Therapy: Patient Compliance, N.Engl.J.Med. 1973, 289(5):249–52). By virtue of being easier to swallow, an oral liquid dosage form of sertraline would offer an alternative to those patients who dislike or have difficulty swallowing tablets or capsules, and would therefore be of considerable benefit in treating those who may be non-compliant for those reasons. Therefore, there is a need in the art for an alternative liquid dosage form of sertraline that has acceptable taste and properties.
Oral concentrate drug products are known in the art and are commercially available. However, these concentrates are conventionally aqueous. For example, NAVANE® Concentrate contains the active ingredient, thiothixene hydrochloride, and the inert ingredients of alcohol, cherry flavor, dextrose, passion fruit flavor, sorbitol solution and water. (Physicians' Desk Reference (PDR), 52nd ed., pages 2192–2193 (1998).) SINEQUAN® Concentrate contains the active ingredient, doxepin hydrochloride, and the inert ingredients of glycerin, methylparaben, peppermint oil, propylparaben and water. (Physicians' Desk Reference (PDR), 52nd ed., pages 2203–2204 (1998).) TRILAFON® Concentrate contains the active ingredient, perphenazine, and the inert ingredients of alcohol, citric acid, flavors, menthol, sodium phosphate, sorbitol, sugar and water. (Physicians' Desk Reference (PDR), 52nd ed., pages 2666–2668 (1998)).